17β-Estradiol Stimulates the Growth of Human Keratinocytes by Inducing Cyclin D2 Expression
Open accessAbstract
Estrogen is reported to prevent age-associated epidermal thinning in the skin. We examined if 17beta-estradiol (E2) may enhance the growth of human keratinocytes, focusing on its effects on the expression of cell cycle-regulatory proteins. E2 enhanced proliferation, bromodeoxyuridine incorporation of keratinocytes, and increased the proportion of cells in the S phase. The E2-induced stimulation of proliferation and bromodeoxyuridine incorporation was suppressed by antisense oligonucleotide against cyclin D2, which induces G1 to S phase progression. E2 increased protein and mRNA levels of cyclin D2, and resultantly enhanced assembly and kinase activities of cyclin D2-cyclin-dependent kinases 4 or 6 complexes. E2 enhanced cyclin D2 promoter activity, and the element homologous to cAMP response element (CRE) on the promoter was responsible for the effect. Cyclin D2 expression was enhanced by antiestrogens, ICI 182,780 and 4-hydroxytamoxifen, and membrane-impermeable bovine serum albumin-conjugated E2, indicating the effects via membrane E2-binding sites. E2 increased the enhancer activity of CRE-like element and the amount of phosphorylated cAMP response element binding protein (CREB) binding this element, and the increases were suppressed by H-89, an inhibitor of cAMP-dependent protein kinase A. H-89 also suppressed E2-induced cyclin D2 expression, proliferation, and bromodeoxyuridine incorporation in keratinocytes. Antisense oligonucleotide against G-protein-coupled receptor GPR30 suppressed the E2-induced increases of phosphorylated CREB, cyclin D2 level, proliferation, and bromodeoxyuridine incorporation in keratinocytes. These results suggest that E2 may stimulate the growth of keratinocytes by inducing cyclin D2 expression via CREB phosphorylation by protein kinase A, dependent on cAMP. These effects of E2 may be mediated via cell surface GPR30.
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Estrogens stimulate proliferation of normal human epidermal keratinocytes.
“Estrogens stimulate the proliferation of NHEKs [209]”
From Steroidogenesis in the skin: Implications for local immune functions (2013) · cites this paper as [209]
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- Authors
- Kanda, N., & Watanabe, S.
- Affiliations
- Teikyo University (JP)
- Corresponding author
- Kanda, Naoko
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2004-08
- Volume
- 123
- Issue
- 2
- Pages
- 319-328
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W2035409551
- Cited by
- 159
- References
- 2
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 7 · 2021: 1 · 2020: 3 · 2019: 9 · 2018: 9 · 2017: 5 · 2016: 9 · 2015: 9 · 2014: 7 · 2013: 12 · 2012: 4
- FWCI
- 4.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- estradiol, keratinocyte proliferation, cyclin D2, GPR30, CREB phosphorylation, protein kinase A, cAMP signaling, cell cycle regulation, CDK4, CDK6, antiestrogens, epidermal thinning, skin aging
- MeSH terms
- Cyclic AMP, Aged, Aging, Cell Division, Cells, Cultured, DNA, Enhancer Elements, Genetic, Estradiol, Female, Humans, Phosphorylation, Promoter Regions, Genetic, Proto-Oncogene Proteins, Receptors, Estrogen, RNA, Messenger, Keratinocytes, Gene Expression, Cyclins, DNA, Antisense, Cyclic AMP Response Element-Binding Protein, Cyclic AMP-Dependent Protein Kinases, Cyclin-Dependent Kinases, Receptors, G-Protein-Coupled, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Cyclin D2
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